The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

Abstract

Despite the success of liver transplantation, long-term complications remain, including de novo malignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.

Effects of maintenance immunosuppression with sirolimus after liver transplant for hepatocellular carcinoma

“…Although we could not directly assess these events in our study, we did observe a non-significant increase in deaths from graft failure in sirolimus users, some of which could potentially be attributable to hepatic artery thrombosis. Higher rates of hyperlipidemia and hyperglycemia have also been observed in liver recipients treated with mTOR inhibitors (24), and among kidney recipients, nephrotoxicity has been observed when sirolimus is used in conjunction with calcineurin inhibitors (25). Of note, another study that used SRTR data to assess outcomes related to sirolimus use in liver recipients, but was not restricted to HCC patients, found that sirolimus was associated with significantly higher mortality among recipients with hepatitis C infection (26).…”

Influence of hepatorenal syndrome on outcome of living donor liver transplantation: A single‐center experience in 357 patients

“…However, long‐term use of calcineurin inhibitor is associated with a significant risk of chronic renal impairment, de novo malignancies and recurrent hepatitis C virus . Meanwhile, accumulating evidence has recently suggested that mechanistic target of rapamycin inhibitors, such as everolimus, showed the potential not only to act against viral replication and the occurrence of malignancy, but also to alleviate nephrotoxicity by allowing calcineurin inhibitor reduction without increasing the rejection rate . Induction of such new immunosuppressants would enable a “tailor‐made” regimen to each case in the near future, hopefully facilitating to improve patient, as well as renal, outcome in HRS.…”

Everolimus Plus Mycophenolate Mofetil as Initial Immunosuppression in Liver Transplantation

“…The immunosuppressive and antiproliferative properties of EVL and its scarce nephrotoxicity and neurotoxicity suggest that it can be used as early immunosuppression after liver transplantation, especially in selected patients with a greater risk of CNI-associated toxicity or of recurrence of the hepatocarcinoma [5]. The potential benefit of the withdrawal or minimization of the CNI will be more evident the sooner it is done or if its use is avoided from the start, before the onset of any possible irreversible pathogenic changes [6].…”